Substituted benzylidene hydrazines as anti-migraine syndrome agents

ABSTRACT

This disclosure relates to substituted hydrazines, e.g. N-(2,6dichlorobenzylidene)-N&#39;&#39;-amidino hydrazine. These compounds are useful in the treatment of the pain of the migraine syndrome.

United States Patent [1 1 Houlihan et al.

[ SUBSTITUTED BENZYLIDENE HYDRAZINES AS ANTI-MIGRAINE SYNDROME AGENTS [75] Inventors: William J. l-loulihan; Robert E.

Manning, both of Mountain Lakes,

[73] Assignee: Sandoz, Inc., B. Hanover, NJ.

[22] Filed: Apr. 29, 1974 [2]] Appl. No.: 465,187

Related U.S. Application Data [63] Continuation-impart of Ser. No. 322,623, Jan. 11,

1973, abandoned.

[52] U.S. Cl. 424/326 [51] Int. Cl. A61K 27/00 [58] Field of Search 424/326; 260/564 F [451 July 22,1975

[56] References Cited UNITED STATES PATENTS 3,591,636 7/1971 Houlihan et a1. 424/326 3,658,993 4/1972 Kodama et a1 424/326 Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-Gerald D. Sharkin; Robert S. Honor; Walter F. Jewell 10 Claims, No Drawings wherein R, and R are independently hydrogen, halo having an atomic weight of 19 to 36, e.g., chloro or fluoro, methyl, or trifluoromethyl,

R is hydrogen,

R, is hydrogen or OH, or

R and R together are -(CH provided that at least one of R, or R is other than hy drogen, and pharmaceutically acceptable acid addition salts thereof.

The compounds of formula (I) above are known and may be prepared according to methods disclosed in the literature from known materials, for example, see U.S. Pat. No. 3,516,995, U.S. Pat. No. 3,591,636 and U.S. Pat. No. 3,658,993. The compounds offormula (I) may also be described as 2 and/or 6substituted benzylideneaminoguanidines. The present invention only contemplates the novel use of such compounds in pharmaceutical applications, particularly in the treatment of the pain of the migraine syndrome. The above mentioned activity of these compounds is indicated by their activity in the cat given typically 0.01 to 1 mg/kg of active compound intravenously and tested for its constrictive effect upon blood flow. The arterial segments of the cat in which blood flowis to be measured are exposed, and a tight ligature is tied around the upper portion ofthe artery and the lower portion cannulated with saline-filled plastic tubing of sufficient diameter to snugly enter the artery. The other end of the tubing is connected to another previously cannulated artery from which blood flows under arterial pressure into the arterial segment which is under study. A blood flow transducer is interposed in the tubing to measure the flow. A pressure transducer is connected lateral to the flow in order to measure the driving pressure. From 0.0001 to 0.01 mg/kg of Ergotamine Tartrate or Vasopressin are first injected intravenously to serve as a reference. The active agent is then injected intravenously and the resistance to flow and the effects of the active agent on resistance are measured by calculating the resistance to flow (R') as R Pressure/Flow, expressed as percent change in resistance (R).

The effect of the compounds I m the aboveindicated test is similar to that of the known anti-migraine syndrome drug Catapresan".

For such usage, the compounds may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers. They may be administered in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs and parenterally as solutions, suspensions, dispersions, emulsions and the like, e.g. a sterile injectable aqueous solution. The compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Similarly, oral liquids, e.g., suspensions may contain the active ingredient in admix ture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate) wetting agents (lecithin, polyoxyethylene stea rate and polyoxyethylene sorbitan mono-oleate) and preservatives (ethyl-o-hydroxybenzoate). Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. The injectable compositions are formulated as known in the art. These pharmaceutical preparations may contain up to about of the active ingredient in combination with the carrier or adjuvant.

Furthermore, the compounds of formula (I) may be similarly administered in the form of their non'toxic pharmaceutically acceptable acid addition salts. Such salts possess the same order of activity as the free base, which are readily prepared by reacting the base with an appropriate acid and, accordingly, are included within the scope of the invention. Representative of such salts are the mineral acid salts, such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfonate, benzene-sulfonate, maleate, malate, tartrate, methanesulfonate, cyclohexylsulfamate and the like.

The effective dosage of active ingredient employed in the alleviation of the pain of the migraine syndrome may vary depending on the particular compound employed, the manner of administering and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of formula (I) are administered at a daily dosage of from about 0.0001 milligrams to about 10 milligrams p.o. per kilogram of animal body weight. The compounds are preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 0.007 milligrams to about 50 milligrams. Dosage forms suitable for oral use comprise from about 0.002 to about 25 milligrams of the active compound in intimate adand tablets containing from about 1 to 10 milligrams of r the active ingredient.

EXAMPLES 1 AND 2 Tablets and Capsules Suitable for Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating the pain of the migraine syndrome at a dose of one tablet or capsule 2 to 4 times a day.

Weight (mg) Ingredient tablct capsule l-(2.o-dichlorobenzylideneamino)- 3-hydroxyguanidine hydrochloride l l0 tragucanth l0 lactose 237.5 290 corn starch 25 talcum l5 magnesium stcaratc 2.5

Total 300 mg 300 mg.

Tablets and capsules useful in the treatment of the pain of the migraine syndrome may be prepared in a similar manner using compounds a) to c) and e) and f) above as the active ingredient.

EXAMPLES 3 AND 4 Sterile Suspension for Injection and Oral Liquid Suspension The following pharmaceutical compositions are formulated with the indicated amount of active agent using conventional techniques. The injectable suspension and the oral liquid suspension represent formulations useful as unit doses which may be administered in the treatment of the pain of the migraine syndrome. The injectable suspension is suitable for administration once a day whereas the oral liquid suspension is suit ably administered 2 to 4 times per day for this purpose.

Ingredients Weight (mg) injectable liquid suspension suspension l-(2,6-dichlorobenzylidene- -Continued Ingredients Weight (mg) injectable liquid suspension suspension amino)-3-hydroxyguanidine hydrochloride 10 sodium carboxy methyl cellulose. U.S.P. l.25 12.5 methyl cellulose 0.4 polyvinylpyrrolidone 5 lecithin 3 benzyl alcohol 0.01 magnesium aluminum silicate 47.5 flavor q.s color q.s mathyl paraben, U.S.P. 4.5 propyl paraben, U.S.P. 1.0 polysorbate 80 (eg. Tween 80). USP 5 sorbitol solution, USP 2,500 buffer agent to adjust pH for desired stability q.s. q.s. water for q.s. to

injection. 5 ml q.s. to 1 ml Similarly, injectable suspensions and oral liquid suspension useful in the treatment of the pain of the migraine syndrome may be prepared in the same manner using compounds a) to c) and e) and f) above as the active ingredient.

What is claimed is: y

l. The method of treating the pain of the migraine syndrome, which comprises administering to a mammal in need of said treatment a migraine syndrome pain re lieving effective amount of a compound of the formula NR: CH=NNH- NHR,

wherein R and R are independently hydrogen, halo having an atomic weight of 19 to 36, methyl, or trifluoromethyl, R is hydrogen, R is hydrogen-or OH, or R and R together are (CH provided that one of R or R is other than hydrogen, or a pharmaceutically acceptable acid addition salt thereof.

2. The method of claim 1 wherein the compound is administered at a daily dosage of from 0.007 milligrams to about 50 milligrams.

3. The method of claim 1 wherein the compound is administered in a unit dosage form comprising said compound to the extent of from 0.002 to about 12.5 milligrams per unit dosage.

4. The method of claim 1 wherein the compound is l-(2,6-dichlorobenzylideneamino)-3- hydroxyguanidine.

5. The method of claim 1 wherein the compound is l-( 2,6-dichlorobenzylideneamino )guanidine.

6. The method of treating the pain of the migraine syndrome, which comprises administering orally to a mammal in need of said treatment a migraine syndrome 6 pain relieving effective amount of a compound of the 7. The method of claim 6 wherein the compound is formula: administered at a daily dosage of from 0.007 milligrams to about 50 milligrams.

8. The method of claim 6 wherein the compound is administered in a unit dosage form comprising said compound to the extent of from 0.002 to about 12.5

milligrams per unit dosage.

NHR4 9. The method of claim 6 wherein the compound is R l-(2,-dichlorobenzylideneamino)-3- 2 hydroxyguanidine.

10. The method of claim 6 wherein the compound is 1-(2,6-dichlorobenzylideneamino)guanidine.

wherein R R R R and the proviso are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof. 

1. THE METHOD OF TREATING THE PAIN OF THE MIGRAINE SYNDROME, WHICH COMPRISES ADMINISTERING TO A MAMMAL IN NEED OF SID TREATMENT A MIGRAINE SYNDROME PAIN RELIEVING EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA
 2. The method of claim 1 wherein the compound is administered at a daily dosage of from 0.007 milligrams to about 50 milligrams.
 3. The method of claim 1 wherein the compound is administered in a unit dosage form comprising said compound to the extent of from 0.002 to about 12.5 milligrams per unit dosage.
 4. The method of claim 1 wherein the compound is 1-(2,6-dichlorobenzylideneamino)-3-hydroxyguanidine.
 5. The method of claim 1 wherein the compound is 1-(2,6-dichlorobenzylideneamino)guanidine.
 6. The method of treating the pain of the migraine syndrome, which comprises administering orally to a mammal in need of said treatment a migraine syndrome pain relieving effective amount of a compound of the formula:
 7. The method of claim 6 wherein the compound is administered at a daily dosage of from 0.007 milligrams to about 50 milligrams.
 8. The method of claim 6 wherein the compound is administered in a unit dosage form comprising said compound to the extent of from 0.002 to about 12.5 milligrams per unit dosage.
 9. The method of claim 6 wherein the compound is 1-(2,6-dichlorobenzylideneamino)-3-hydroxyguanidine.
 10. The method of claim 6 wherein the compound is 1-(2,6-dichlorobenzylideneamino)guanidine. 